Microneedle device and method for manufacturing the same

Abstract

To manufacture a microneedle device capable of carrying and administering a larger amount of physiologically active substance per microneedle.SOLUTION: There is provided a method for manufacturing microneedle devices, the method including a step of applying a coating liquid to a microneedle, the coating liquid containing a physiologically active substance and a sulfated polysaccharide. The microneedle device manufactured by the method includes a substrate 2, microneedles 4 disposed on the substrate, and coatings 6 formed on the microneedles, the coating containing a physiologically active substance and a sulfated polysaccharide.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] The present invention relates to a microneedle device and a method for manufacturing the same.

Background Art

[0002] Transdermal administration using a microneedle device is known as a form for administering a drug. The microneedle device enables transdermal drug administration by piercing microneedles into the stratum corneum, which is the outermost layer of the skin, to form fine pores through which the drug can pass. The microneedle device includes, for example, a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles, and the coating contains a physiologically active substance (for example, Patent Document 1).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Summary of the Invention

Problems to be Solved by the Invention

[0004] In order to suppress skin irritation caused by the use of a microneedle device, it is conceivable to reduce the number (density) of microneedles per unit area. However, when the number of microneedles is reduced, the amount of the physiologically active substance that can be administered accordingly decreases, so that sufficient drug efficacy may not be exhibited. Therefore, an object of the present invention is to manufacture a microneedle device that can carry and administer more physiologically active substances per microneedle.

Means for Solving the Problems

[0005] A microneedle device according to one embodiment of the present invention includes a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles, and the coating contains a physiologically active substance and a sulfated polysaccharide.

[0006] The sulfated polysaccharide may be one or more sulfated polysaccharides selected from the group consisting of chondroitin sulfate, carrageenan, fucoidan, ascophyllan, heparin, heparan sulfate, heparin analogs, keratan sulfate, funoran, porphyran, agaropectin, fursellaran, laminaran sulfate, glucuronoxylorhamnan sulfate, xylarabinogalactan sulfate, glucuronoxylorhamnogalactan sulfate, arabinan sulfate, arabinorhamnan sulfate, sulfated dextran, sulfated pentosan, sulfated curdlan, and sulfated cellulose, and salts thereof, and is preferably sodium chondroitin sulfate. The physiologically active substance may be dexmedetomidine or a pharmaceutically acceptable salt thereof. The amount of the sulfated polysaccharide relative to 100 parts by mass of the coating may be 0.5 part by mass or more. The mass ratio of the sulfated polysaccharide to the physiologically active substance may be 0.01 to 0.36, preferably 0.011 to 0.222, and more preferably 0.089 to 0.222. The microneedles may be disposed on the substrate at a needle density of 10 needles / cm 2 or more and 850 needles / cm 2 or less. The amount of the physiologically active substance supported per microneedle may be 390 ng or more.

[0007] A method for manufacturing a microneedle device according to one embodiment of the present invention includes a step of applying a coating solution to the microneedles, and the coating solution contains a physiologically active substance and a sulfated polysaccharide. The microneedle device includes a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles.

[0008] The sulfated polysaccharide may be one or more sulfated polysaccharides selected from the group consisting of chondroitin sulfate, carrageenan, fucoidan, ascophyllan, heparin, heparan sulfate, heparin-like substances, keratan sulfate, funoran, porphyran, agaropectin, fursellaran, laminaran sulfate, glucuronoxylorhamnan sulfate, xylarabinogalactan sulfate, glucuronoxylorhamnogalactan sulfate, arabinan sulfate, arabinorhamnan sulfate, sulfated dextran, sulfated pentosan, sulfated curdlan, and sulfated cellulose, and salts thereof, and is preferably sodium chondroitin sulfate. The bioactive substance may be dexmedetomidine or a pharmaceutically acceptable salt thereof. The concentration of the sulfated polysaccharide in the coating solution may be 0.1% by mass or more. The mass ratio of the sulfated polysaccharide to the bioactive substance in the coating solution may be 0.01 to 0.36, preferably 0.011 to 0.222, and more preferably 0.089 to 0.222.

Advantages of the Invention

[0009] According to the present invention, it is possible to produce a microneedle device that can carry and administer more bioactive substances per microneedle.

Brief Description of the Drawings

[0010]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7

Figure 8

Mode for Carrying Out the Invention

[0011] The method for manufacturing a micro-needle device according to one embodiment of the present invention includes a step of applying a coating solution to the micro-needles (coating step). After the coating step, a step of drying the coating solution (drying step) may be carried out. Here, the micro-needle device is a device including a substrate, micro-needles disposed on the substrate, and a coating formed on the micro-needles.

[0012] An embodiment of the microneedle device according to the present invention is shown in FIG. 1. The microneedle device 10 includes a substrate 2, a plurality of microneedles 4 disposed on the main surface of the substrate 2, and a coating 6 formed on the microneedles 4. In this specification, a configuration in which a plurality of microneedles 4 are arranged on the substrate 2 is referred to as a microneedle array. Details of the coating 6 will be described later.

[0013] The substrate 2 is a base for supporting the microneedles 4. The shape of the substrate 2 is not particularly limited, and may be, for example, rectangular or circular, and the main surface may be flat or curved. The area of the substrate 2 is, for example, 0.5 cm 2 ~10 cm 2 、0.5 cm 2 ~5 cm 2 、1 cm 2 ~5 cm 2 、0.5 cm 2 ~3 cm 2 、or 1 cm 2 ~3 cm 2 and may be. The thickness of the substrate 2 may be 50 μm to 2000 μm, 300 μm to 1200 μm, or 500 μm to 1000 μm.

[0014] The microneedle 4 may be a needle-shaped convex structure. The shape of the microneedle 4 may be, for example, a polygonal pyramid shape such as a square pyramid shape or a conical shape. The microneedle 4 is a micro-structure, and the length (height) H of the microneedle 4 in the vertical direction with respect to the main surface of the substrate 2 M is preferably, for example, 50 μm to 600 μm, 100 μm to 500 μm, or 300 μm to 500 μm.

[0015] The microneedles 4 are arranged on the main surface of the substrate, for example, in a square lattice pattern, a rectangular lattice pattern, a rhombic lattice pattern, a 45° staggered pattern, or a 60° staggered pattern.

[0016] The density (needle density) at which the microneedles 4 are arranged on the substrate 2 is represented by the number of microneedles 4 per unit area in the region substantially provided with the microneedles 4. The region substantially provided with the microneedles 4 is a region obtained by connecting the outermost microneedles 4 among the plurality of microneedles 4 arranged in the microneedle device 10. From the viewpoint of introducing more physiologically active substances into the skin, the needle density is, for example, 10 needles / cm 2 or more, 50 needles / cm 2 or more, or 100 needles / cm 2 or more. From the viewpoint of reducing skin irritation, the needle density is, for example, 850 needles / cm 2 or less, 500 needles / cm 2 or less, 200 needles / cm 2 or less, or 160 needles / cm 2 or less.

[0017] Examples of the material of the substrate 2 or the microneedles 4 include silicon, silicon dioxide, ceramics, metals, polysaccharides, and synthetic or natural resin materials. Examples of the polysaccharides include pullulan, chitin, and chitosan. The resin material may be, for example, a biodegradable polymer such as polylactic acid, polyglycolide, polylactic acid-co-polyglycolide, polycaprolactone, polyurethane, polyamino acid (for example, poly-γ-aminobutyric acid), etc., or a non-degradable polymer such as polycarbonate, polymethacrylic acid, ethylene vinyl acetate, polytetrafluoroethylene, polyoxymethylene, cyclic olefin copolymer, etc.

[0018] In the coating step in the method for manufacturing the microneedle device 10 according to one embodiment of the present invention, a coating liquid is applied to the microneedles 4. The coating liquid contains a physiologically active substance and a sulfated polysaccharide.

[0019] The physiologically active substance is a substance that exerts a therapeutic or preventive effect on the subject to which it is administered. The physiologically active substance may be, for example, a peptide, a protein, a nucleic acid such as DNA and RNA, a sugar, a glycoprotein, or other high-molecular or low-molecular compounds.

[0020] Specific examples of the physiologically active substance include dexmedetomidine, interferon α, interferon β for multiple sclerosis, erythropoietin, follitropin β, follitropin α, G-CSF, GM-CSF, human chorionic gonadotropin, luteinizing hormone, follicle-stimulating hormone (FSH), salmon calcitonin, glucagon, GNRH antagonist, insulin, LHRH (luteinizing hormone-releasing hormone), human growth hormone, parathyroid hormone (PTH), filgrastim, somatropin, incretin, GLP-1 analogs (e.g., exenatide, liraglutide, lixisenatide, albiglutide, and taspoglutide), snake venom peptide analogs, γ-globulin, Japanese encephalitis vaccine, hepatitis B vaccine, rotavirus vaccine, Alzheimer's disease vaccine, arteriosclerosis vaccine, cancer vaccine, nicotine vaccine, diphtheria vaccine, tetanus vaccine, pertussis vaccine, Lyme disease vaccine, rabies vaccine, pneumococcal vaccine, yellow fever vaccine, cholera vaccine, smallpox vaccine, tuberculosis vaccine, rubella vaccine, measles vaccine, influenza vaccine, mumps vaccine, botulinum vaccine, herpes virus vaccine, and pharmaceutically acceptable salts thereof. The physiologically active substance may be, for example, dexmedetomidine or dexmedetomidine hydrochloride. The coating solution may contain one kind of physiologically active substance or may contain a plurality of kinds of physiologically active substances.

[0021] In the present invention, the sulfated polysaccharide is a component (carrier) that helps to support the coating solution on the microneedle 4. The sulfated polysaccharide has an affinity for skin tissue and is excellent in improving the absorbability of the physiologically active substance into the skin. The sulfated polysaccharide is a polysaccharide in which sulfuric acid is bonded to a hydroxyl group or an amino group.

[0022] The polysaccharide in the sulfated polysaccharide may be a natural polysaccharide, or may be a semi-synthetic or synthetic polysaccharide. The main structure of the polysaccharide is preferably a mucopolysaccharide (also known as glycosaminoglycan). A mucopolysaccharide is a heteropolysaccharide having uronic acid and hexosamine as sugar units. The sulfate moiety in the sulfated polysaccharide may be in the form of a free acid or may form a salt. The sulfate moiety is preferably a monovalent metal salt, particularly a sodium salt. The coating solution may contain one kind of sulfated polysaccharide or may contain a plurality of kinds of sulfated polysaccharides.

[0023] Examples of natural or biologically-derived sulfated polysaccharides include chondroitin sulfate, carrageenan, fucoidan, ascophyllan, heparin, heparan sulfate, heparin-like substances (heparanoids), keratan sulfate, funoran, porphyran, agaropectin, fursellulan, laminaran sulfate, glucuronoxylorhamnan sulfate, xylarabinogalactan sulfate, glucuronoxylorhamnogalactan sulfate, arabinan sulfate, and arabinorhamnan sulfate, and salts thereof. Examples of semi-synthetic or synthetic sulfated polysaccharides include sulfated dextran, sulfated pentosan, sulfated curdlan, and sulfated cellulose, and salts thereof.

[0024] Examples of sulfated polysaccharides having a mucopolysaccharide as the main structure include chondroitin sulfate, heparin, heparan sulfate, heparanoids, and keratan sulfate, and salts thereof. Among these, chondroitin sulfate and its salts are more preferred. The scope of chondroitin sulfate includes any of chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chondroitin sulfate D, chondroitin sulfate E, chondroitin sulfate H, and chondroitin sulfate K.

[0025] Examples of salts of chondroitin sulfate include salts with alkali metals such as sodium and potassium, salts with alkaline earth metals such as calcium and magnesium, salts with other metals such as aluminum, and salts with organic bases. The salt of chondroitin sulfate is preferably an alkali metal salt of chondroitin sulfate, more preferably sodium chondroitin sulfate.

[0026] The origin of chondroitin sulfate and its salts is not limited. Chondroitin sulfate and its salts can be obtained, for example, from mammals such as pigs, fish such as salmon and sharks, or microorganisms.

[0027] Due to the presence of sulfate groups, sulfated polysaccharides tend to have common physical, chemical, and physiological properties. As the proportion of sulfate groups in the sulfated polysaccharide increases, the affinity for water, water retention, and thickening effect increase, but the proportion of sulfate groups in the sulfated polysaccharide is not particularly limited. The number of sulfate groups in the sulfated polysaccharide may be 0.25N to 2N, preferably 0.5N to 1.5N, per N sugar units mainly constituting the polysaccharide. When the polysaccharide has two main sugar units, the number of sulfate groups may be 0.5 to 4, preferably 1 to 3, per disaccharide unit mainly constituting the polysaccharide.

[0028] The viscosity average molecular weight of the sulfated polysaccharide may be, for example, 1000 Da to 500000 Da, 1000 Da to 100000 Da, or 7000 Da to 40000 Da, but is not limited thereto. The viscosity average molecular weight can be calculated using the Mark-Houwink-Sakurada equation from the limiting viscosity determined in accordance with the first method of viscosity measurement in the general test method of the Fifteenth Revised Japanese Pharmacopoeia: capillary viscometer method.

[0029] The coating solution contains one or more solvents for dissolving the physiologically active substance and the sulfated polysaccharide. Examples of the solvent include water, polyhydric alcohol, lower alcohol, and triacetin. Water is suitable because it dissolves the sulfated polysaccharide well. Also, water is suitable in that it also dissolves dexmedetomidine or its pharmaceutically acceptable salt well.

[0030] In addition to the above-mentioned physiologically active substance, sulfated polysaccharide, and solvent, the coating solution may further contain other components (for example, stabilizers, pH adjusters, components that promote the transfer of the physiologically active substance into the blood, fats and oils, or inorganic substances). However, it is preferable that the coating solution does not contain surfactants, monosaccharides, and disaccharides. Surfactants, monosaccharides, and disaccharides may reduce the surface tension and viscosity of the coating solution and may reduce the amount of the physiologically active substance carried per micro needle 4.

[0031] The stabilizer has, for example, the effect of suppressing the oxidation of each component by oxygen and photooxidation and stabilizing the physiologically active substance. Examples of the stabilizer are L-cysteine, sodium pyrosulfite, sodium bisulfite, ascorbic acid, ethylenediaminetetraacetic acid (EDTA) or its salts, or dibutylhydroxytoluene (BHT). These stabilizers may be used alone or in combination of a plurality.

[0032] As the pH adjuster, those commonly used in the art can be used. Examples of the pH adjuster include inorganic acids or organic acids, alkalis, salts, amino acids, or combinations thereof.

[0033] The concentration of the sulfated polysaccharide in the coating solution may be, for example, 0.1% by mass or more, 0.5% by mass or more, 1% by mass or more, 1.3% by mass or more, 1.5% by mass or more, 2% by mass or more, 3% by mass or more, or 4% by mass or more, and may also be 20% by mass or less, 16% by mass or less, 15% by mass or less, 14% by mass or less, 13% by mass or less, 12% by mass or less, 11% by mass or less, 10% by mass or less, 9% by mass or less, or 8% by mass or less. From the viewpoint of manufacturing the micro needle device 10 capable of carrying and administering more physiologically active substances per micro needle, the concentration of the sulfated polysaccharide in the coating solution may be, for example, 1.3% by mass to 11% by mass, 1.5% by mass to 10% by mass, 2% by mass to 10% by mass, 0.5% by mass to 16% by mass, 0.5% by mass to 10% by mass, or 4.0% by mass to 10% by mass.

[0034] The concentration of the bioactive substance in the coating solution can be adjusted according to the type of the bioactive substance, the purpose of treatment, the state of the disease, the state of the patient, and the nature of the solvent. The concentration of the bioactive substance in the coating solution may be, for example, 0.01% by mass to 90% by mass, 0.1% by mass to 80% by mass, or 1% by mass to 70% by mass.

[0035] The mass ratio of the sulfated polysaccharide to the bioactive substance in the coating solution may be, for example, 0.01 or more, 0.02 or more, 0.025 or more, 0.03 or more, 0.035 or more, 0.04 or more, 0.05 or more, or 0.08 or more, and may also be 0.36 or less, 0.35 or less, 0.3 or less, 0.27 or less, 0.26 or less, 0.24 or less, 0.23 or less, 0.20 or less, 0.18 or less, or 0.17 or less. When the bioactive substance is dexmedetomidine or a pharmaceutically acceptable salt thereof, the above mass ratio is preferably 0.011 to 0.222, 0.044 to 0.222, or 0.089 to 0.222.

[0036] The total amount of other components other than the above bioactive substance, sulfated polysaccharide, and solvent may be, for example, 80% by mass or less, 60% by mass or less, 30% by mass or less, or 20% by mass or less based on the total mass of the coating solution. The coating solution may not contain other components other than the above bioactive substance, sulfated polysaccharide, and solvent.

[0037] The concentration of each component contained in the coating solution can be measured, for example, by liquid chromatography. In addition, the concentration of components other than the bioactive substance can also be calculated based on the concentration of the bioactive substance measured by liquid chromatography and the ratio of each component at the time of formulating the coating solution.

[0038] From the viewpoint of applying more coating liquid by the micro needle 4 and from the viewpoint of forming the coating 6 on the tip portion of the micro needle 4, the viscosity of the coating liquid is preferably 500 mPa·s to 30,000 mPa·s, more preferably 1,000 mPa·s to 10,000 mPa·s at 25°C. From the same viewpoint, the surface tension of the coating liquid is preferably 10 mN / m to 100 mN / m, more preferably 20 mN / m to 80 mN / m.

[0039] The method of applying the coating liquid to the micro needle 4 is not particularly limited, and for example, the coating liquid can be applied by inkjet coating or dip coating. Among them, dip coating is preferred. In dip coating, the micro needle 4 is immersed to a certain depth in a reservoir in which the coating liquid is stored, and then the micro needle 4 is pulled out from the reservoir, whereby the coating liquid is applied to the micro needle 4.

[0040] Here, according to the coating liquid according to the present invention containing the sulfated polysaccharide, a large amount of the coating liquid can be applied to the micro needle 4. Therefore, it is possible to produce the micro needle device 10 that can carry and administer more physiologically active substances per micro needle.

[0041] The amount of the coating liquid applied to the micro needle 4 can be adjusted, for example, by the depth of immersion of the micro needle 4 in the case of coating by dip coating. Here, the depth of immersion of the micro needle 4 indicates the distance from the apex of the immersed micro needle 4 to the surface of the coating liquid. The depth of immersion depends on the length H of the micro needle 4 M but, for example, H MIt may be 1 / 2 or less. However, among the physiologically active substances contained in the coating 6 formed by drying the coating solution, the physiologically active substances contained in the portion formed at the base portion of the microneedle 4 are less likely to be introduced into the skin than the physiologically active substances contained in the portion formed at the tip portion of the microneedle 4. Therefore, it is preferable to apply more coating solution mainly to the tip portion of the microneedle 4. Here, as described later, the tip portion of the microneedle 4 means a portion where the length measured in the direction perpendicular to the main surface of the substrate 2 (that is, the base portion) from the apex of the microneedle 4 is, for example, 50% or less of the length H of the microneedle 4. M represents a portion having a length within 50% of

[0042] In the drying step after the coating step, the coating solution can be dried to form the coating 6 on the microneedle 4. Here, drying the coating solution means volatilizing part or all of the solvent contained in the coating solution. Drying of the coating solution can be performed by, for example, methods such as air drying, vacuum drying, freeze drying, or combinations thereof. A preferred drying method is air drying.

[0043] Here, since the coating solution according to the present invention containing sulfated polysaccharide has high viscosity and surface tension, it is possible to further reduce the spreading of the coating solution downward due to gravity before or during drying of the coating solution. Therefore, even when the coating solution is dried with the microneedle array placed so that the microneedle 4 faces upward, the coating 6 can be formed mainly on the tip portion of the microneedle 4.

[0044] The coating step and the drying step can be repeated. By repeating these steps, the amount of the formed coating 6 can be further increased.

[0045] The micro-needle device 10 according to one embodiment of the present invention, produced by the above method, comprises a coating 6 containing a physiologically active substance and a sulfated polysaccharide on the micro-needle 4.

[0046] Details of the micro-needle array, the physiologically active substance, and the sulfated polysaccharide that make up the micro-needle device 10 are as described above. The coating 6 is obtained by removing part or all of the solvent from the above-described coating solution. Therefore, the above-described coating solution and the coating 6 have the same components except for the solvent.

[0047] The amount of the sulfated polysaccharide may be, for example, 0.5 parts by mass or more, 1 part by mass or more, 1.9 parts by mass or more, 2 parts by mass or more, 2.5 parts by mass or more, 3 parts by mass or more, 3.5 parts by mass or more, 5.0 parts by mass or more, or 8.0 parts by mass or more, with respect to 100 parts by mass of the coating 6, and may also be 27 parts by mass or less, 25 parts by mass or less, 22 parts by mass or less, 21 parts by mass or less, 20 parts by mass or less, 19 parts by mass or less, 18 parts by mass or less, 17 parts by mass or less, 14 parts by mass or less, or 13 parts by mass or less.

[0048] The amount of the physiologically active substance may be, for example, 99 parts by mass or less, 95 parts by mass or less, 92 parts by mass or less, 90 parts by mass or less, 89 parts by mass or less, 88 parts by mass or less, 87.5 parts by mass or less, or 87 parts by mass or less, with respect to 100 parts by mass of the coating 6, and may also be 65 parts by mass or more, 70 parts by mass or more, 72 parts by mass or more, 73 parts by mass or more, 74 parts by mass or more, 75 parts by mass or more, 77 parts by mass or more, 78 parts by mass or more, 79 parts by mass or more, or 81 parts by mass or more.

[0049] In the coating 6, the mass ratio of the sulfated polysaccharide to the physiologically active substance may be, for example, 0.01 or more, 0.02 or more, 0.025 or more, 0.03 or more, 0.035 or more, 0.04 or more, 0.05 or more, or 0.08 or more, and may also be 0.36 or less, 0.35 or less, 0.3 or less, 0.27 or less, 0.26 or less, 0.24 or less, 0.23 or less, 0.20 or less, 0.18 or less, or 0.17 or less. When the physiologically active substance is dexmedetomidine or a pharmaceutically acceptable salt thereof, the above mass ratio is preferably, for example, 0.011 to 0.222, 0.044 to 0.222, or 0.089 to 0.222.

[0050] The total amount of other components other than the above-mentioned physiologically active substance, sulfated polysaccharide, and solvent may be, for example, 95 parts by mass or less, 75 parts by mass or less, 50 parts by mass or less, or 30 parts by mass or less with respect to 100 parts by mass of the solid content in the coating 6. In this specification, the solid content refers to the components remaining when the solvent is removed from the coating solution.

[0051] The preferable loading amount of the physiologically active substance per microneedle 4 depends on the type of the physiologically active substance, the purpose of treatment, the state of the disease, and the state of the patient. When the physiologically active substance is dexmedetomidine or a pharmaceutically acceptable salt thereof, from the viewpoint of exerting sufficient medicinal effects, the loading amount of dexmedetomidine or a pharmaceutically acceptable salt thereof per microneedle 4 is preferably 390 ng or more, 451 ng or more, or 670 ng or more. There is no particular upper limit to the loading amount of the physiologically active substance per microneedle 4, but it may be, for example, 2 μg or less, 1 μg or less, 755 ng or less, 545 ng or less, or 500 ng or less. The loading amount of the sulfated polysaccharide per microneedle 4 may be, for example, 15 ng to 100 ng, 21 ng to 97 ng, 5 ng to 149 ng, or 67 ng to 149 ng. The loading amount of the coating 6 per microneedle 4 may be, for example, 490 ng to 700 ng, 516 ng to 642 ng, 456 ng to 836 ng, or 819 ng to 836 ng.

[0052] The amount of each component contained in the coating 6 can be measured, for example, by a liquid chromatography method. Also, the amount of components other than the physiologically active substance can be calculated based on the amount of the physiologically active substance measured by the liquid chromatography method and the ratio of each component at the time of formulating the coating solution. The amount of each component supported per one micro-needle 4 can be obtained by dividing the value measured or calculated in this way by the number of micro-needles.

[0053] When there are a plurality of micro-needles 4, the coating 6 may be formed on all the micro-needles 4, or may be formed only on some of the micro-needles 4. The coating 6 may be formed only on the tip portion of the micro-needle 4, or may be formed so as to cover the entire micro-needle 4. The coating 6 is preferably formed on the tip portion of the micro-needle 4. Here, the tip portion of the micro-needle 4 means a portion where the length measured in the direction perpendicular to the main surface of the substrate 2 (that is, the base portion) from the apex of the micro-needle 4 is within 50%, within 40%, within 30%, or within 20% of the length H M of the micro-needle 4. The average thickness of the coating 6 may be less than 50 μm, and may be 1 μm to 30 μm.

Example

[0054] <Test Example 1> Comparison of Carriers The components shown in Tables 1 and 2 were mixed to prepare coating solutions 1 to 4. In the tables, γ-PGA is γ-polyglutamic acid. As chondroitin sulfate sodium (hereinafter sometimes referred to as CSNa), a pharmaceutical grade product of Maruha Nichiro Corporation was used. As pullulan, a pharmaceutical product of Hayashibara Co., Ltd. was used. As γ-PGA, a product of Nippon Polyglu Co., Ltd. was used. As polyvinyl alcohol, "Kuraray Poval PVA-205" (saponification degree: about 87.0 mol% to 89.0 mol%, degree of polymerization: about 500) of Kuraray Co., Ltd. was used.

Table 1

[0055]

Table 2

[0056] For coating liquids 1 and 2, the contact angle, surface tension, and viscosity with respect to the polylactic acid micro needles were measured. The contact angle was measured by the droplet method (θ / 2 method) (temperature 23°C to 25°C). The surface tension was calculated by the pendant drop method using the empirical formula of Andreas et al. (temperature 24°C). The viscosity was determined from the pressure loss in the capillary flow path (temperature 23°C to 25°C). The results are shown in Table 3.

[0057]

Table 3

[0058] As shown in Table 3, there was no significant difference in surface tension and viscosity between the coating liquid containing sodium chondroitin sulfate and the coating liquid containing pullulan.

[0059] Next, a polylactic acid micro needle array having micro needles with a density of 156 needles / cm² in a 1 cm² area and the shape of each micro needle being a square pyramid with a height of 500 μm was prepared, and the micro needles were immersed in coating liquids 1 to 4 to a depth of about 140 μm. After pulling up the micro needles from the coating liquid, the solvents of coating liquids 1 to 4 on the micro needles were dried to obtain micro needle devices 1 to 4. 2 of the region with a density of 156 needles / cm 2 and the shape of each micro needle is a square pyramid with a height of 500 μm. After pulling up the micro needles from the coating liquid, the solvents of coating liquids 1 to 4 on the micro needles were dried to obtain micro needle devices 1 to 4.

[0060] After drying the solvent, the amount of dexmedetomidine hydrochloride in the coating formed on the micro needles was quantified by high performance liquid chromatography, and the amount of the carrier and the amount of the coating per micro needle were calculated therefrom. The results are shown in Table 4 and Figure 2.

[0061]

Table 4

[0062] By using sodium chondroitin sulfate as a carrier, a microneedle device capable of carrying more bioactive substances per microneedle was able to be manufactured as compared with the case of using pullulan (nonionic polysaccharide), polyvinyl alcohol (nonionic polymer), and γ-PGA.

[0063] <Test Example 2> Comparison of the Composition of the Coating Solution Dexmedetomidine hydrochloride, sodium chondroitin sulfate, L-cysteine (stabilizer), and water for injection were mixed to prepare coating solutions 5 to 13 (Examples) shown in Table 5. The details of the sodium chondroitin sulfate used were the same as in Test Example 1. In a region of 1 cm 2 with a density of 156 needles / cm 2 A polylactic acid microneedle array equipped with microneedles and having a square pyramid shape with a height of 500 μm for each microneedle was prepared, and the microneedles were immersed in coating solutions 5 to 13 to a depth of about 140 μm. After pulling up the microneedles from the coating solution, the solvent of the coating solutions 5 to 13 on the microneedles was dried to obtain microneedle devices 5 to 13 (Examples).

[0064]

Table 5

[0065] After drying the solvent, the amount of dexmedetomidine hydrochloride in the coating formed on the microneedles was quantified by high performance liquid chromatography, and from this, the amount of the carrier and the amount of the coating per microneedle were calculated. The results are shown in Table 6.

[0066]

Table 6

[0067] Figure 3 is a graph plotting the amount of coating per micro needle, as well as the amounts of dexmedetomidine hydrochloride and the carrier contained therein, against the concentration (mass %) of sodium chondroitin sulfate in the coating solution. As shown in Figure 3, by adding sodium chondroitin sulfate to the coating solution at a concentration within a specific range, a micro needle device capable of carrying more dexmedetomidine hydrochloride per micro needle could be manufactured.

[0068] Note that Figure 4 is a graph in which the horizontal axis of Figure 3 is changed to the concentration (mass %) in terms of solid content of dexmedetomidine hydrochloride in the coating solution. The concentration in terms of solid content of dexmedetomidine hydrochloride means the ratio of dexmedetomidine hydrochloride in the total amount of solids (dexmedetomidine hydrochloride, sodium chondroitin sulfate, and L-cysteine) in the coating solution.

[0069] Figure 5 is a graph plotting the amount of dexmedetomidine hydrochloride (DEX amount) carried per micro needle with the mass ratio of sodium chondroitin sulfate to dexmedetomidine hydrochloride (CSNa / DEX ratio) on the horizontal axis. In Figure 5, the solid line indicates the measured values and the dashed line indicates the theoretical values. The theoretical values indicate the DEX amount estimated to be contained in the coating when the maximum amount of coating is carried per micro needle. The theoretical values were calculated assuming that the amount of coating carried per micro needle (562 ng) when the maximum value of the amount of dexmedetomidine hydrochloride in Table 6 (486 ng / needle) was obtained is the maximum amount of coating that can be carried per micro needle. The formula used for calculating the theoretical values is as follows. Theoretical value of DEX amount (ng / needle) = 562 (ng / needle) × Concentration (mass %) of dexmedetomidine hydrochloride in terms of solid content in the coating solution / 100 As shown in Fig. 5, when the CSNa / DEX ratio was in the range of 0.044 to 0.222, although there was some variation, the measured values and the theoretical values were substantially in agreement. On the other hand, when the CSNa / DEX ratio exceeded 0.222, the measured values were lower than the theoretical values, and the difference in values increased with the increase in the CSNa / DEX ratio. From this, it is presumed that at a CSNa / DEX ratio exceeding 0.222, some change occurred in the physical properties of the coating solution, and this change acted in a direction that inhibited the increase in the amount of DEX carried on the microneedles.

[0070] <Test Example 3> Comparison of the Composition of the Coating Solution Dexmedetomidine hydrochloride (bioactive substance), chondroitin sulfate sodium (carrier), and water for injection were mixed to prepare coating solutions 14 to 23 (Examples) shown in Table 7. The details of the chondroitin sulfate sodium used were the same as in Test Example 1. In a region of 1 cm 2 with a density of 156 needles / cm 2 A polylactic acid microneedle array having microneedles with a shape of a square pyramid with a height of 500 μm was prepared, and the microneedles were immersed in coating solutions 14 to 23 to a depth of about 140 μm. After pulling up the microneedles from the coating solution, the solvent of the coating solutions 14 to 23 on the microneedles was dried to obtain microneedle devices 14 to 23.

[0071]

Table 7

[0072] After drying the solvent, the amount of dexmedetomidine hydrochloride in the coating formed on the microneedles was quantified by high performance liquid chromatography, and from this, the amount of the carrier and the amount of the coating per microneedle were calculated. The results are shown in Table 8.

[0073]

Table 8

[0074] Figure 6 is a graph plotting the amount of coating per micro-needle, as well as the amount of dexmedetomidine hydrochloride and the carrier contained therein, against the concentration (mass %) of sodium chondroitin sulfate in the coating solution. As shown in Figure 6, by adding sodium chondroitin sulfate to the coating solution at a concentration within a specific range, it was possible to manufacture a micro-needle device that can carry more dexmedetomidine hydrochloride per micro-needle.

[0075] Note that Figure 7 is a graph with the horizontal axis of Figure 6 changed to the concentration (mass %) in terms of solid content of dexmedetomidine hydrochloride in the coating solution. The concentration in terms of solid content of dexmedetomidine hydrochloride means the ratio of dexmedetomidine hydrochloride in the total amount of solid content (dexmedetomidine hydrochloride and sodium chondroitin sulfate) in the coating solution.

[0076] Figure 8 is a graph plotting the amount of dexmedetomidine hydrochloride (DEX amount) carried per micro-needle with the mass ratio of sodium chondroitin sulfate to dexmedetomidine hydrochloride (CSNa / DEX ratio) on the horizontal axis. In Figure 8, the solid line indicates the measured value and the dashed line indicates the theoretical value. The theoretical value indicates the DEX amount estimated to be contained in the coating when the maximum amount of coating is carried per micro-needle. The theoretical value was calculated assuming that the amount of coating carried per micro-needle (822 ng) when the maximum value of the amount of dexmedetomidine hydrochloride (755 ng / needle) in Table 8 was obtained is the maximum amount of coating that can be carried per micro-needle. The formula used for calculating the theoretical value is as follows. Theoretical value of DEX amount (ng / needle) = 822 (ng / needle) × Concentration (mass %) of dexmedetomidine hydrochloride in terms of solid content in the coating solution / 100 As shown in Fig. 8, when the CSNa / DEX ratio was between 0.089 and 0.222, the measured values substantially agreed with the theoretical values. On the other hand, when the CSNa / DEX ratio exceeded 0.222, the measured values were lower than the theoretical values, and the difference in values increased with the increase in the CSNa / DEX ratio. From this, it is presumed that at CSNa / DEX ratios exceeding 0.222, some change occurred in the physical properties of the coating solution, and this change acts in a direction that inhibits the increase in the amount of DEX carried on the microneedles.

Explanation of reference numerals

[0077] 2... substrate, 4... microneedle, 6... coating, 10... microneedle device.

Claims

1. In a microneedle device comprising a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles, a method for loading more dexmedetomidine or a pharmaceutically acceptable salt thereof per microneedle, comprising: A method comprising the step of including dexmedetomidine or a pharmaceutically acceptable salt thereof and sodium chondroitin sulfate in a coating solution for forming the coating.

2. The method according to claim 1, wherein the mass ratio of sodium chondroitin sulfate to dexmedetomidine or a pharmaceutically acceptable salt thereof is 0.011 to 0.

222.

3. The method according to claim 2, wherein the mass ratio of sodium chondroitin sulfate to dexmedetomidine or a pharmaceutically acceptable salt thereof is 0.089 to 0.

222.

4. In the micro-needle device, the micro-needles are arranged on the substrate at a needle density of 10 needles / cm ２ or more and 850 needles / cm ２ or less, the method according to any one of claims 1 to 3.

5. The method according to any one of claims 1 to 4, wherein the loading amount of dexmedetomidine or a pharmaceutically acceptable salt thereof per microneedle is 390 ng or more.

6. The method according to any one of claims 1 to 5, wherein the material of the microneedle is silicon, silicon dioxide, ceramic, metal, polysaccharide, or resin.

7. A method for manufacturing a microneedle device comprising a substrate, microneedles disposed on the substrate, and a coating formed on the microneedles, comprising: A step of applying a coating solution to the microneedles by dip coating, The coating solution contains dexmedetomidine or a pharmaceutically acceptable salt thereof, sodium chondroitin sulfate, and water, The method wherein the mass ratio of sodium chondroitin sulfate to water in the coating solution is 0.009 to 0.

41.

8. The method according to claim 7, wherein the concentration of sodium chondroitin sulfate in the coating solution is 0.1% by mass or more.

9. The method according to claim 7 or 8, wherein the mass ratio of sodium chondroitin sulfate to dexmedetomidine or a pharmaceutically acceptable salt thereof in the coating solution is 0.011 to 0.

222.

10. The method according to claim 9, wherein the mass ratio of sodium chondroitin sulfate to dexmedetomidine or a pharmaceutically acceptable salt thereof in the coating solution is 0.089 to 0.

222.

11. The method according to any one of claims 7 to 10, wherein the material of the microneedle is silicon, silicon dioxide, ceramic, metal, polysaccharide, or resin.

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